Mazzo, Francesca;
Butnaru, Ioana;
Grubisha, Olivera;
Ficulle, Elena;
Sanger, Helen;
Fitzgerald, Griffin;
Pan, Feng;
... Sher, Emanuele; + view all
(2022)
Metabotropic glutamate receptors modulate exocytotic tau release and propagation.
The Journal of Pharmacology and Experimental Therapeutics
10.1124/jpet.122.001307.
(In press).
Preview |
Text
JPET Schiavo.pdf - Accepted Version Download (727kB) | Preview |
Abstract
Using synaptosomes purified from the brains of two transgenic mouse models overexpressing mutated human tau (TgP301S and Tg4510) and brains of patients with sporadic Alzheimer's disease, we showed that aggregated and hyperphosphorylated tau was both present in purified synaptosomes and released in a calcium- and SNAP25-dependent manner. In all mouse and human synaptosomal preparations, tau release was inhibited by the selective mGlu2/3 receptor agonist LY379268, an effect prevented by the selective mGlu2/3 antagonist LY341495. LY379268 was also able to block pathological tau propagation between primary neurons in an in vitro microfluidic cellular model. These novel results are transformational for our understanding of the molecular mechanisms mediating tau release and propagation at synaptic terminals in Alzheimer's disease and suggest these processes could be inhibited therapeutically by the selective activation of presynaptic G-protein-coupled receptors. Significance Statement Pathological tau release and propagation is a key neuropathological event underlying cognitive decline in Alzheimer's disease patients. In this paper we describe the role of regulated exocytosis, and the SNARE protein SNAP25, in mediating tau release from rodent and human synaptosomes. We also show that a selective mGluR2/3 agonist is highly effective in blocking tau release from synaptosomes and tau propagation between neurons, opening the way to the discovery of novel therapeutic approaches to this devastating disease.
| Type: | Article |
|---|---|
| Title: | Metabotropic glutamate receptors modulate exocytotic tau release and propagation |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1124/jpet.122.001307 |
| Publisher version: | https://doi.org/10.1124/jpet.122.001307 |
| Language: | English |
| Additional information: | This research was funded in whole, or in part, by the Wellcome Trust [107116/Z/15/Z and 223022/Z/21/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. |
| Keywords: | Alzheimer's Disease, Metabotropic glutamate, botulinum, brain/CNS |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10156580 |
Archive Staff Only
 |
View Item |
